Transportation of sublingual antigens across sublingual ductal epithelial cells to the ductal antigen‐presenting cells in mice

Nagai, Yoshinori; Shiraishi, Daisuke; Tanaka, Yukinori; Nagasawa, Yoji; Ohwada, Shyuichi; Shimauchi, Hidetoshi; Aso, Hisashi; Endo, Yasuo; Sugawara, Shunji

doi:10.1111/cea.12329

Cited by 26 publications

(26 citation statements)

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“…In our investigation, we observed Si beads accumulating in the apical cytoplasm of some cells lining the sublingual ducts but not in the mandibular ducts. This observation is supported by a previous report concerning the role of the sublingual ductal system in incorporating and delivering sublingual antigens to ductal antigen-presenting cells [18]. Interestingly, in this previous report M cells were observed in the gastrointestinal mucosa and demonstrated the ability to take up antigen by phagocytosis [30, 31].…”

Section: Discussionsupporting

confidence: 85%

“…Furthermore, a recent report revealed the role of APCs in sublingual ductal epithelial cells in the transportation of sublingual antigen. This was shown using soluble antigens such as ovalbumin and particulate antigens such as E. coli, latex beads (Lt) and silica beads (Si) [18]. Moreover, it has been revealed that bacterial infection of the salivary glands may result from bacteria ascending through salivary gland ducts and stasis of salivary flow through the ducts [19].…”

Section: Introductionmentioning

confidence: 99%

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Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

Elewa

Mizoguchi

Ichii

et al. 2018

Preprint

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Background24 Recently, sublingual immunotherapy (SLIT) has been used as a safe and efficient method for the 25 treatment of and immunization against asthma and various allergies. However, the routes of antigen 26 uptake through the mucosa of the oral cavity remain incompletely understood, as do the roles of sex 27 and age in the process. For this purpose, to elucidate the mechanism and efficacy of SLIT among 28 different sexes and ages microbeads were dripped into the sublingual region to mimic antigen uptake 29 by the sublingual mucosa.30 Methods 31 Twenty microliters of either phosphate buffered saline (PBS) or fluorescently labelled microbeads 32 (latex and silica beads) were placed under the tongue of both male and female C57BL/6 mice at young 33 (3 months) and old (6 months) ages. The lower jaw was examined 30 min after administration, and 34 beads were detected with a fluorescence stereomicroscope. Morphological observations of the 35 mucosa of the fluorescent areas were made with scanning electron microscopy (SEM) and an all-in-36 one light fluorescence microscope (LM). Fluorescence intensity was compared between both sexes 37 and ages.38 Results 39 Stereomicroscopic observation revealed fluorescent illuminations in three compartments of the 40 sublingual mucosa: the sublingual caruncles (SC), the oral rostral mucosa (OR) and the buccal 3 41 mucosa (BM). Interestingly, the fluorescence intensity tended to be higher among females than 42 among males in the SC region in particular. However, there were no significant age-related 43 differences. SEM and LM revealed beads in the lumina of both mandibular ducts and sublingual ducts 44 (Sd). Additionally, the apical cytoplasm of some Sd cells contained silica beads. However, there were 45 no specification in the OR mucosa or BM.46 Conclusions 47 This study reveals the major role Sd play in local immunity via the antigen uptake mechanisms.48 Furthermore, our data suggest that the efficacy of SLIT in humans could be affected by sex.49 Keywords: antigen uptake, beads, sublingual immunotherapy, sublingual caruncles, C57BL/6 mice 4 50 INTRODUCTION 51 In both humans and animals, the prevalence of allergic diseases such as seasonal rhinitis and atopic 52 dermatitis has increased substantially in recent decades [1][2][3]. The symptoms accompanying such 53 allergic conditions range in severity. Mild symptoms such as itching and sneezing may cause 54 disturbances in the patient's daily life and affect productivity, while severe ones such as anaphylactic 55 shock can be life-threatening [4]. Therefore, establishing countermeasures against the development 56 of allergic conditions is an important issue in both the medical and veterinary fields.57 Treatment for allergic diseases is currently based primarily on symptomatic therapy to reduce 58 inflammation; antihistamines and steroids are widely used for this [5, 6]. However, immune induction 59 therapy has attracted attention in recent years. Among them is sublingual immunotherapy (SLIT), 60 which is allergen-specific. In SLI...

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

Elewa

Mizoguchi

Ichii

et al. 2018

Preprint

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“…Supporting this route also for PM‐allergoids is the response obtained in submandibular LNs, the primary draining lymph nodes of sublingual tissue 24. In this sense, besides antigen penetration across the sublingual epithelial barrier, an active capture by intraepithelial DCs25 or through the ductal epithelial cells26 has been described, even for particulate antigens, silica beads, or microbes 26. In fact, bigger structures than PM‐allergoids, like particles of different sizes15, 27 or whole cell bacteria,28, 29 have also been successfully used for immunization through the sublingual route.…”

Section: Discussionmentioning

confidence: 92%

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

Soria

López-Relaño

Viñuela

et al. 2018

Allergy

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BackgroundPolymerized allergoids coupled to nonoxidized mannan (PM‐allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM‐allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM‐allergoids administered sublingually in comparison with native allergens.MethodsThree immunization protocols (4‐8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells.ResultsA quick antibody response and higher IgG2a/IgE ratio were observed with PM‐allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL‐4 ratio with a quick IL‐10 production by submandibular LN cells. An increase in CD4+ CD25high FOXP3+ Treg cells was detected in LNs and spleen of mice treated with PM‐allergoids. These allergoids were better captured than native allergens by antigen‐presenting (CD45+ MHC‐II +) cells obtained from the sublingual mucosa, including DCs (CD11b+) and macrophages (CD64+). Importantly, all the differential effects induced by PM‐allergoids were abolished when using oxidized instead of nonoxidized PM‐allergoids.ConclusionOur results demonstrate for the first time that PM‐allergoids administered through the sublingual route promote the generation of Th1 and FOXP3+ Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen‐presenting cells.

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“…Compared to other routes, the sublingual and buccal routes have the potential to induce mucosal immune responses in a broad range of tissues (Table 1) as described in more detail in Section 2.2 ('Mucosal immune responses'). Nagai et al (2014) recently reported the transport of sublingual antigens across sublingual ductal epithelial cells to ductal APCs in mice [14]. Since different studies failed to detect specific sampling cells (or M-like structures) in the sublingual or buccal mucosa [14,15], it seems most likely that antigens cross the ductal epithelium via paracellular and transcellular pathways [14].…”

Section: Implications For Mucosal Vaccine Delivery and Comparison Witmentioning

confidence: 99%

“…Nagai et al (2014) recently reported the transport of sublingual antigens across sublingual ductal epithelial cells to ductal APCs in mice [14]. Since different studies failed to detect specific sampling cells (or M-like structures) in the sublingual or buccal mucosa [14,15], it seems most likely that antigens cross the ductal epithelium via paracellular and transcellular pathways [14]. So, probably the efficiency of vaccine delivery via these routes is directly related to the permeability of the mucosal membrane.…”

Section: Implications For Mucosal Vaccine Delivery and Comparison Witmentioning

confidence: 99%

Buccal and sublingual vaccine delivery

Kraan

Vrieling

Czerkinsky

et al. 2014

Journal of Controlled Release

170

135

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Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery.

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Transportation of sublingual antigens across sublingual ductal epithelial cells to the ductal antigen‐presenting cells in mice

Abstract: This study reveals that sublingual antigens can be transported across sublingual ductal epithelial cells to the ductal APCs. If the system is the same in humans as in mice, the ductal APCs may prove to be important target cells for SLIT.

Cited by 26 publications

References 25 publications

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice

Buccal and sublingual vaccine delivery

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